Novel crystalline forms of parecoxib sodium

ABSTRACT

The present invention relates to novel crystalline forms of parecoxib sodium, to processes for their preparation and to pharmaceutical compositions containing them.

FIELD OF THE INVENTION

The present invention relates to novel crystalline forms of parecoxibsodium, to processes for their preparation and to pharmaceuticalcompositions containing them.

BACKGROUND OF THE INVENTION

Parecoxib sodium of formula (1):

or N-[4-(5-Methyl-3-phenylisoxazol-4-yl)phenylsulfonyl]propionamidesodium salt is a highly selective and potent cyclooxygenase-2 inhibitorin human whole blood and useful in the treatment of arthritis and pain.The other therapeutic utilities of parecoxib and related compounds weredisclosed in WO 9738986.

Crystalline forms of parecoxib sodium have not been reported in theliterature. So, there is a need for stable polymorphs of parecoxibsodium for better pharmaceutical preparations.

We have discovered six stable novel crystalline forms of parecoxibsodium.

The object of the present invention is to provide stable novelcrystalline forms of parecoxib sodium, processes for preparing theseforms and pharmaceutical compositions containing them.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention, there is provided a novelcrystalline form of parecoxib sodium (hereinafter referred to asparecoxib sodium form I), which is characterized by an x-ray powderdiffraction pattern having peaks expressed as 2θ at about 5.7, 8.3,10.4, 17.4, 21.0 and 23.2 degrees. FIG. 1 shows typical form I x-raypowder diffraction pattern.

In accordance with the present invention, there is provided a novelcrystalline form of parecoxib sodium (hereinafter referred to asparecoxib sodium form II), which is characterized by an x-ray powderdiffraction pattern having peaks expressed as 2θ at about 5.4, 6.8, 7.9,10.6, 16.2, 17.1, 19.5, 20.4 and 22.4 degrees. FIG. 2 shows typical formII x-ray powder diffraction pattern.

In accordance with the present invention, there is provided a novelcrystalline form of parecoxib sodium (hereinafter referred to asparecoxib sodium form III), which is characterized by an x-ray powderdiffraction pattern having peaks expressed as 2θ at about 5.3, 5.9, 6.6,7.8, 8.3, 10.7, 11.9, 12.2, 16.1, 19.5, 20.0, 21.6, 23.4 and 30.1degrees. FIG. 3 shows typical form III x-ray powder diffraction pattern.

In accordance with the present invention, there is provided a novelcrystalline form of parecoxib sodium (hereinafter referred to asparecoxib sodium form IV), which is characterized by an x-ray powderdiffraction pattern having peaks expressed as 20 at about 5.2, 7.9,12.1, 17.3, 17.9, 22.5, 23.4 and 27.1 degrees. FIG. 4 shows typical formIV x-ray powder diffraction pattern.

In accordance with the present invention, there is provided a novelcrystalline form of parecoxib sodium (hereinafter referred to asparecoxib sodium form V), which is characterized by an x-ray powderdiffraction pattern having peaks expressed as 20 at about 6.5, 7.7, 9.3,10.6, 13.2, 15.5, 15.9, 17.4, 17.8, 20.2, 21.7, 22.1, 22.8, 23.4 and24.3 degrees. FIG. 5 shows typical form V x-ray powder diffractionpattern.

In accordance with the present invention, there is provided a novelcrystalline form of parecoxib sodium (hereinafter referred to asparecoxib sodium form VI), which is characterized by an x-ray powderdiffraction pattern having peaks expressed as 2θ at about 5.4, 7.9, 9.5,11.9, 18.1, 18.6, 20.9, 30.2 and 32.1 degrees. FIG. 6 shows typical formIV x-ray powder diffraction pattern.

In accordance with the present invention, there is provided processesfor the preparation the novel forms I-VI of parecoxib sodium.

A process is provided for preparing parecoxib sodium form I from eitherparecoxib or parecoxib sodium. In this process either parecoxib sodiumin any crystalline form or parecoxib and an sodium metal carrier aremixed with an alcohol solvent and then parecoxib sodium form I isisolated from the mixture.

Suitable alcohol solvents are methanol, ethanol, isopropyl alcohol,tert-butyl alcohol, n-butyl alcohol; and a mixture thereof. Preferredalcohol solvents are ethanol, methanol and isopropyl alcohol. Othersolvents may also be mixed with the alcohol solvent as long as parecoxibform I can be isolated from the mixture.

A process is provided for preparing parecoxib sodium form II from eitherparecoxib or parecoxib sodium. In this process either parecoxib sodiumin any crystalline form or parecoxib and an sodium metal carrier aremixed with acetonitrile and then parecoxib sodium form II is isolatedfrom the mixture.

A process is provided for preparing parecoxib sodium form III fromeither parecoxib or parecoxib sodium. In this process either parecoxibsodium in any crystalline form or parecoxib and an sodium metal carrierare mixed with tetrahydrofuran and then parecoxib sodium form III isisolated from the mixture.

A process is provided for preparing parecoxib sodium form IV from eitherparecoxib or parecoxib sodium. In this process either parecoxib sodiumin any crystalline form or parecoxib and an sodium metal carrier aremixed with an ether solvent and then parecoxib sodium form IV isisolated from the mixture.

Suitable ether solvents are diethyl ether, diisopropyl ether, methyltert-butyl ether; and a mixture thereof.

A process is provided for preparing parecoxib sodium form V from eitherparecoxib or parecoxib sodium. In this process either parecoxib sodiumin any crystalline form or parecoxib and an sodium metal carrier aremixed with an ester solvent and then parecoxib sodium form V is isolatedfrom the mixture.

Suitable ester solvents are ethyl acetate (which is prererred), methylacetate, isopropyl acetate, tert-butyl acetate, ethyl formate, methylformate; and a mixture thereof.

A process is provided for preparing parecoxib sodium form VI from eitherparecoxib or parecoxib sodium. In this process either parecoxib sodiumin any crystalline form or parecoxib and an sodium metal carrier aremixed with a ketone solvent and then parecoxib sodium form VI isisolated from the mixture.

Suitable ketone solvents are acetone (which is preferred), diethylketone, methyl ethyl ketone, methyl isobutyl ketone, methyl propylketone; and a mixture thereof.

Through out this specification, sodium metal carriers are sodium ethylhexanoate, sodium hydroxide, and the like.

The mixing step of the processes of the present invention may beaccomplished by, for example, slurrying or stirring. Isolation can beaccomplished by, for example, filtration or centrifugation of thereaction mixture.

In accordance with the present invention, there is provided apharmaceutical composition comprising parecoxib sodium form I and apharmaceutically acceptable carrier or diluent.

In accordance with the present invention, there is provided apharmaceutical composition comprising parecoxib sodium form II and apharmaceutically acceptable carrier or diluent.

In accordance with the present invention, there is provided apharmaceutical composition comprising parecoxib sodium form III and apharmaceutically acceptable carrier or diluent.

In accordance with the present invention, there is provided apharmaceutical composition comprising parecoxib sodium form IV and apharmaceutically acceptable carrier or diluent.

In accordance with the present invention, there is provided apharmaceutical composition comprising parecoxib sodium form V and apharmaceutically acceptable carrier or diluent.

In accordance with the present invention, there is provided apharmaceutical composition comprising parecoxib sodium form VI and apharmaceutically acceptable carrier or diluent.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a x-ray powder diffraction spectrum of parecoxib sodium formI.

FIG. 2 is a x-ray powder diffraction spectrum of parecoxib sodium formII.

FIG. 3 is a x-ray powder diffraction spectrum of parecoxib sodium form111.

FIG. 4 is a x-ray powder diffraction spectrum of parecoxib sodium formIV.

FIG. 5 is a x-ray powder diffraction spectrum of parecoxib sodium formV.

FIG. 6 is a x-ray powder diffraction spectrum of parecoxib sodium formVI.

x-Ray powder diffraction spectrum was measured on a Siemens D5000 x-raypowder diffractometer having a copper-Kα radiation.

The invention will now be further described by the following examples,which are illustrative rather than limiting.

EXAMPLE 1

Parecoxib (5.0 gm) is dissolved in ethanol (25 ml) and then sodiumhydroxide (0.5 gm) is added. The contents are maintained for 2 hours at25° C. to 30° C., cooled to 0° C. and the separated crystals arecollected by filtration to give 4.5 gm of parecoxib sodium form I.

EXAMPLE 2

Parecoxib (5.0 gm) is dissolved in acetonitrile (25 ml) and then sodiumhydroxide (0.5 gm) is added. The contents are maintained for 2 hours 30minutes at 25° C. to 27° C., cooled to 0° C. and the separated crystalsare collected by filtration to give 4.0 gm of parecoxib sodium form II.

EXAMPLE 3

Parecoxib sodium form II (10 gm) is mixed with isopropyl alcohol (50ml), the contents are maintained for 2 hours at 25° C. to 30° C., cooledto 0° C. and solid is collected by filtration to give parecoxib sodiumform I in quantitative yield.

EXAMPLE 4

Parecoxib (5.0 gm) is dissolved in tetrahydrofuran (30 ml) and thensodium hydroxide (0.5 gm) is added. The contents are maintained for 1hours 30 minutes at 20° C. to 25° C., cooled to 0° C. and the separatedcrystals are collected by filtration to give 3.0 gm of parecoxib sodiumform III.

EXAMPLE 5

Parecoxib sodium form I (10 gm) is mixed with tetrahydrofuran (60 ml),the contents are stirred for 3 hours at 25° C. to 30° C., cooled to 0°C. and solid is collected by filtration to give 9.5 gm of parecoxibsodium form III.

EXAMPLE 6

Parecoxib (5.0 gm), methyl tert-butyl ether (25 ml) and sodium hydroxide(0.5 gm) are mixed. The contents are maintained for 3 hours at 28° C. to30° C., cooled to 20° C. and the separated crystals are collected byfiltration to give 4.5 gm of parecoxib sodium form IV.

EXAMPLE 7

Parecoxib (5.0 gm) is dissolved in ethyl acetate (30 ml) and then sodiumhydroxide (0.5 gm) is added. The contents are maintained for 18 hours at28° C. to 30° C. The separated crystals are collected by filtration togive 4.0 gm of parecoxib sodium form V.

EXAMPLE 8

Parecoxib sodium form II (5 gm) is mixed with ethyl acetate (25 ml), thecontents are maintained for 2 hours at 25° C. to 30° C., cooled to 0° C.and solid is collected by filtration to give 4.8 gm of parecoxib sodiumform V.

EXAMPLE 9

Parecoxib (5.0 gm) is dissolved in acetone (25 ml) and then sodiumhydroxide (0.5 gm) is added. The contents are maintained for 2 hours at57° C. to 60° C., cooled to 25° C. and the separated crystals arecollected by filtration to give 4.0 gm of parecoxib sodium form VI.

1. A crystalline parecoxib sodium form I, characterized by an x-raypowder diffraction pattern having peaks expressed as 2θ at about 5.7,8.3, 10.4, 17.4, 21.0 and 23.2 degrees.
 2. The crystalline parecoxibsodium form I as defined in claim 1, further characterized by an x-raypowder diffraction pattern as in FIG.
 1. 3. A crystalline parecoxibsodium form II, characterized by an x-ray powder diffraction patternhaving peaks expressed as 2θ at about 5.4, 6.8, 7.9, 10.6, 16.2, 17.1,19.5, 20.4 and 22.4 degrees.
 4. The crystalline parecoxib sodium form IIas defined in claim 3, further characterized by an x-ray powderdiffraction pattern as in FIG.
 2. 5. A crystalline parecoxib sodium formIII, characterized by an x-ray powder diffraction pattern having peaksexpressed as 2θ at about 5.3, 5.9, 6.6, 7.8, 8.3, 10.7, 11.9, 12.2,16.1, 19.5, 20.0, 21.6, 23.4 and 30.1 degrees.
 6. The crystallineparecoxib sodium form III as defined in claim 5, further characterizedby an x-ray powder diffraction pattern as in FIG.
 3. 7. A crystallineparecoxib sodium form IV, characterized by an x-ray powder diffractionpattern having peaks expressed as 2θ at about 5.2, 7.9, 12.1, 17.3,17.9, 22.5, 23.4 and 27.1 degrees.
 8. The crystalline parecoxib sodiumform IV as defined in claim 7, further characterized by an x-ray powderdiffraction pattern as in FIG.
 4. 9. A crystalline parecoxib sodium formV, characterized by an x-ray powder diffraction pattern having peaksexpressed as 2θ at about 6.5, 7.7, 9.3, 10.6, 13.2, 15.5, 15.9, 17.4,17.8, 20.2, 21.7, 22.1, 22.8, 23.4 and 24.3 degrees.
 10. The crystallineparecoxib sodium form V as defined in claim 9, further characterized byan x-ray powder diffraction pattern as in FIG.
 5. 11. A crystallineparecoxib sodium form VI, characterized by an x-ray powder diffractionpattern having peaks expressed as 2θ at about 5.4, 7.9, 9.5, 11.9, 18.1,18.6, 20.9, 30.2 and 32.1 degrees.
 12. The crystalline parecoxib sodiumform VI as defined in claim 11, further characterized by an x-ray powderdiffraction pattern as in FIG.
 6. 13. A process for preparing parecoxibsodium form I as defined in claim 1, which comprises the steps of: a)mixing together i) either 1) parecoxib sodium or 2) parecoxib and asodium metal carrier, and ii) an alcohol solvent; and b) isolatingparecoxib sodium form I from the mixture; wherein the alcohol solvent isselected from the group consisting of methanol, ethanol, isopropylalcohol, tert-butyl alcohol and n-butyl alcohol.
 14. The processaccording to claim 13, wherein the sodium metal carrier is sodiumhydroxide.
 15. The process according to claim 13, wherein the alcoholsolvent is ethanol.
 16. A process for preparation of parecoxib sodiumform II as defined in claim 3, which comprises the steps of: a) mixingtogether i) either 1) parecoxib sodium or 2) parecoxib and a sodiummetal carrier, and ii) acetonitrile; and b) isolating parecoxib sodiumform II from the mixture.
 17. The process according to claim 16, whereinsodium metal carrier is sodium hydroxide.
 18. A process for preparationof parecoxib sodium form III as defined in claim 5, which comprises thesteps of: a) mixing together i) either 1) parecoxib sodium or 2)parecoxib and a sodium metal carrier, and ii) tetrahydrofuran; and b)isolating parecoxib sodium form III from the mixture.
 19. The processaccording to claim 18, wherein the sodium metal carrier is sodiumhydroxide.
 20. A process for preparation of parecoxib sodium form IV asdefined in claim 7, which comprises the steps of: a) mixing together i)either 1) parecoxib sodium or 2) parecoxib and a sodium metal carrier,and ii) an ether solvent; and b) isolating parecoxib sodium form IV fromthe mixture; wherein the ether solvent is selected from the groupconsisting of diethyl ether, diisopropyl ether and methyl tert-butylether.
 21. The process according to claim 20, wherein sodium metalcarrier is sodium hydroxide.
 22. The process according to claim 20,wherein the ether solvent is methyl tert-butyl ether.
 23. A process forpreparation of parecoxib sodium form V as defined in claim 9, whichcomprises the steps of: a) mixing together i) either 1) parecoxib sodiumor 2) parecoxib and a sodium metal carrier, and ii) an ester solvent;and b) isolating parecoxib sodium form V from the mixture; wherein theester solvent is selected from the group consisting of ethyl acetate,methyl acetate, isopropyl acetate, tert-butyl acetate, ethyl formate andmethyl formate.
 24. The process according to claim 23, wherein sodiummetal carrier is sodium hydroxide.
 25. The process according to claim23, wherein the ether solvent is ethyl acetate.
 26. A process forpreparation of parecoxib sodium form VI as defined in claim 11, whichcomprises the steps of: a) mixing together i) either 1) parecoxib sodiumor 2) parecoxib and a sodium metal carrier, and ii) a ketone solvent;and b) isolating parecoxib sodium form VI from the mixture; wherein theketone solvent is selected from the group consisting of acetone, diethylketone, methyl ethyl ketone, methyl isobutyl ketone and methyl propylketone.
 27. The process according to claim 26, wherein sodium metalcarrier is sodium hydroxide.
 28. The process according to claim 26,wherein the ketone solvent is acetone.
 29. The process according toclaim 13, wherein parecoxib sodium is selected from the group consistingof form II of claim 3, form III of claim 5, form IV of claim 7, form Vof claim 9 and form VI of claim
 11. 30. The process according to claim16, wherein parecoxib sodium is selected from the group consisting ofform I of claim 1, form III of claim 5, form IV of claim 7, form V ofclaim 9 and form VI of claim
 11. 31. The process according to claim 18,wherein parecoxib sodium is selected from the group consisting of form Iof claim 1, form II of claim 3, form IV of claim 7, form V of claim 9and form VI of claim
 11. 32. The process according to claim 20, whereinparecoxib sodium is selected from the group consisting of form I ofclaim 1, form II of claim 3, form III of claim 5, form V of claim 9 andform VI of claim
 11. 33. The process according to claim 23, whereinparecoxib sodium is selected from the group consisting of form I ofclaim 1, form II of claim 3, form III of claim 5, form IV of claim 7 andform VI of claim
 11. 34. The process according to claim 26, whereinparecoxib sodium is selected from the group consisting of form I ofclaim 1, form II of claim 3, form III of claim 5, form IV of claim 7 andform V of claim
 9. 35. A pharmaceutical composition comprising parecoxibsodium form I of claim 1 and a pharmaceutically acceptable carrier ordiluent.
 36. A pharmaceutical composition comprising parecoxib sodiumform II of claim 3 and a pharmaceutically acceptable carrier or diluent.37. A pharmaceutical composition comprising parecoxib sodium form III ofclaim 5 and a pharmaceutically acceptable carrier or diluent.
 38. Apharmaceutical composition comprising parecoxib sodium form IV of claim7 and a pharmaceutically acceptable carrier or diluent.
 39. Apharmaceutical composition comprising parecoxib sodium form V of claim 9and a pharmaceutically acceptable carrier or diluent.
 40. Apharmaceutical composition comprising parecoxib sodium form VI of claim11 and a pharmaceutically acceptable carrier or diluent.